WO1995021163A1

WO1995021163A1 - Pyridonecarboxylic acid derivative substituted by bicyclic amino group, ester thereof, salt thereof, and bicyclic amine as intermediate therefor

Info

Publication number: WO1995021163A1
Application number: PCT/JP1995/000135
Authority: WO
Inventors: Masato Sakamoto; Katsumi Chiba; Yukio Tominaga; Akira Minami
Original assignee: Dainippon Pharmaceutical Co., Ltd.
Priority date: 1994-02-04
Filing date: 1995-02-02
Publication date: 1995-08-10
Also published as: EP0812838A1; US5990106A; DE69526595T2; AU1589695A; DK0812838T3; PT812838E; EP0812838A4; AU699636B2; ATE216993T1; JP2848538B2; EP0812838B1; DE69526595D1; ES2173175T3; JPH10512800A

Abstract

A pyridonecarboxylic acid derivative substituted by a bicyclic amino group represented by the general formula A-Pri (wherein Pri represents a pyridonecarboxylic acid residue; and A represents a bicyclic amino group bonded to the 7-position of the acid or a position corresponding thereto and represented by general formula (C), wherein R1 and R2 are the same or different from each other and each represents hydrogen, lower alkyl or an amino-protecting group; R3 and R4 are the same or different from each other and each represents hydrogen, halogen, cyano, hydroxy, oxo, lower alkoxy or lower alkyl; and n represents an integer of 0 or 1), an ester thereof and a salt thereof. These compounds are useful as an antibacterial. The invention also relates to a bicyclic amine compound as a direct intermediate therefor.

Description

Akira WW.

Pyridonecarboxylic acid derivatives substituted with a bicyclic amino group, esters and salts thereof, and bicyclic amines as intermediates thereof

The present invention relates to a novel compound useful as an antibacterial agent and a bicyclic amide which is a synthetic intermediate thereof. Landscape technology

Various antibacterial pyridonecarboxylic acid derivatives are known. For example, JP-A-64-56673 discloses the following general formula:

[Wherein, R represents a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group or a phenyl group which may have a substituent, and X represents a nitrogen atom or C—A. Where A represents a hydrogen atom or a halogen atom, Y represents a hydrogen atom or a halogen atom, and Z represents the following formula

Which means a hydrogen atom, a lower alkylcarbonyl group, or an acyl group which may be substituted with a halogen atom, and R ₂ , R ₃ , R ₄ and R ₅ are two of which are bonded directly or via a lower alkyl chain to form a ring, the others represent a hydrogen atom, and n represents 0 or 1.

However, when R ₂ and ^ are bonded, they are direct bonds. Wherein R ₄ and R _{5 in} the above formula (A) are linked via an ethylene chain to form a ring. Is not disclosed.

In addition, in the specification of U.S. Patent Application Publication No.

(B)

, / Eight ,

R (CH ₂ ) mR ₂ Wherein Ri is hydrogen, hydroxy, C, -C alkyl, -C ₄ alkyne, oxo, halogen or optionally C, -C ₄ alkyl and Z or C, 1 -C ₄ alkanol, A good amino; R ₂ is azide, hydroxy, C! -C ₄ alkoxy, Ci-C ₄ alkoxycarbonyl, d—C ₄ alkanol or optionally — C ₄ alkyl and / or Ci—C ₄ A is amino which may be substituted by an alkanoyl;

R ₃ is hydrogen or a carboxy protecting group; R ₄ is

C, — C ₄ alkyl, C ₂ -C alkenyl, C ₃ -C cycloalkyl, mono- or difluorophenyl or optionally substituted by halogen and or C, -C ₄ alkyl 5 Or 6-membered heterocyclic group; R ₅

20 is hydrogen, Amino, human Dorokishi or d - be C ₄ alkoxy; R ₆ is halogen; X is CH- (! C - C ₄ Al _{kill), C = CH 2, N-} H or N- ( C, - C ₄ be alkyl Le); Z is an CQ or N; Q is hydrogen, d - C ₄ alkoxy, Nono androgenic, - a C alkyl or Shiano

25; m is an integer of 0 or 1; n and p are each

Is an integer of 1-3) Although the pyridonecarboxylic acid derivative represented by is disclosed, the compound in which n is 0 is not included.

In addition, compounds represented by the following formula are disclosed in Chemical Abstract 66, 37500b (19667) and Japanese Patent Application Laid-Open No. 56-117229.

R

NH

[Wherein, R represents a hydrogen atom or a carboxyl group] A conventional pyridonecarboxylic acid derivative substituted with a bicyclic amino group, such as the compound represented by the above general formula (A) or (B), Although useful as an antibacterial agent, its antibacterial activity, particularly in vivo (in vivo), is not always sufficient.

The present invention has been completed as a result of various studies to develop a pyridonecarboxylic acid derivative with further enhanced antibacterial activity, especially in vivo.

Disclosure of the invention

According to the present invention, there is provided a pyridonecarboxylic acid derivative substituted with a novel bicyclic amino group represented by the following general formula (I), its ester and its salt.

A-P r i (I)

[In the formula, Pri is a pyridonecarboxylic acid residue, and A is a compound represented by the following formula (C) bonded to the 7-position or a position corresponding to the 7-position of the pyridonecarboxylic acid. R ₁

.ヽ

R ₂ — N

Wherein R and R ₂ are the same or different and each represents a hydrogen atom, a lower alkyl group or an amino protecting group, and R ₃ and R ₄ are the same or different Each represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an oxo group, a lower alkoxy group or a lower alkyl group, and n represents an integer of 0 or 1.)

Further, according to the present invention, there is provided a bicyclic amine compound represented by the following general formula (II) and a salt thereof, which are useful as an intermediate of the pyridonecarboxylic acid derivative represented by the general formula (I).

Wherein R,, R ₂ , R ₃ , R ₄ and n have the above-mentioned meanings. )

In the present specification, a pyridonecarboxylic acid residue represented by “P ri” means a group having a skeleton structure represented by the following formula (D) in a molecule.

[In the formula, X, y and z are the same or different and each represents a carbon atom or a nitrogen atom, and w represents a carbon atom.] Also, “position 7 or equivalent position of pyridonecarboxylic acid” Is the position of w in the above formula (D). For example, in the case of a pyridonecarboxylic acid having a quinoline structure and an 8-naphthyridine structure, the 7-position is represented by a pyrid [2,3_d]. In the case of a pyridonecarboxylic acid having a pyrimidine structure, this means the 2-position, and in the case of a pyridonecarboxylic acid having an ofloxacin structure, it means the 10-position.

Therefore, according to the present invention, a pyridonecarboxylic acid derivative substituted with a bicyclic amino group represented by the following general formula (I-A), an ester thereof and a salt thereof are preferably provided. Is done.

(I-A)

[Wherein, R ₅ represents a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl group, or a heterocyclic group (these groups may be further substituted); E or a nitrogen atom, where E is a hydrogen atom, or together with R ₅ forms a bridge represented by —S—CH (CH ₃ ) —, and T is C—Z Or a nitrogen atom, wherein Z represents a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkyl group or a halogeno lower alkyl group, or together with R ₅ In other words, X forms a bridge represented by —〇-CH ₂ —CH (CH ₃ ) —, and X represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or an amino group which may be protected. Where D is C—Y or a nitrogen atom, where Y is water The atom or a halogen atom and meaning _{_{taste, 1¾ 1, 1¾ 2, 1}} ^ 3, 1 ^ 4 and n that have a meaning of the]

The structural feature of the compound (I) of the present invention is that a specific bicyclic amino group represented by the formula (C) is selected as a substituent at the 7-position or a position equivalent to the 7-position of pyridonecarboxylic acid. I did it. Next, terms relating to substituents and the like in this specification will be described.

The “halogen atom” is not particularly limited, but fluorine, chlorine or bromine is preferred. The term "lower", unless stated otherwise, refers to groups containing one to seven carbon atoms. “Lower alkyl” includes, for example, straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and the like, and methyl is preferable. Examples of the “lower alkenyl” include vinyl, aryl, 1-propenyl, and isopropenyl, and vinyl is preferable. "Lower cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, with cyclopropyl being preferred. Examples of “lower alkoxy” include methoxydiethoxy.

"Further optionally substituted lower alkyl group" in the definition of R _5, the substituent of the "further substituted or unprotected lower alkenyl group" or "further optionally substituted lower cycloalkyl group" Is a halogen atom such as fluorine or chlorine. Examples of the substituent in the “optionally substituted phenyl group” include, for example, halogen, lower alkyl, lower alkoxy, hydroxy, nitro, amino And the like. As the “heterocyclic group” in the definition of R ₅ , for example, a heterocycle such as pyrrole, furan, thiophene, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidabur, pyridine, pyridazine, pyrimidine, virazine, etc. Examples include 5- or 6-membered heterocyclic groups containing N, 〇, or S as atoms, and these heterocyclic groups include, for example, halogen, lower alkyl, lower alkoxy, hydroxy, nitro, amino and the like. It may be further substituted.

The term "protecting group" and "amino protecting group" in the "optionally protected amino group" include ordinary deprotecting groups such as hydrolysis or hydrogenolysis. Any substance that can be easily desorbed by the reaction without substantially affecting other structural parts can be employed.

Examples of readily hydrolyzable amino protecting groups that can be easily removed by hydrolysis include ethoxycarbonyl tB0c, butoxycarbonyl, benzyloxycarbonyl, ρ-methoxybenzyloxycarboxy. Oxycarbonyl groups such as benzyl, vinyloxycarbonyl, S- (p-toluenesulfonyl) ethoxycarbonyl; acyl groups such as formyl, acetyl, and trifluoroacetyl; 0-ditrophenylsulfenyl, trimethylsilyl, Tetrahydroviranyl, diphenylphosphinyl and the like.

Examples of the easily hydrolyzable amino-protecting group which is easily eliminated by hydrogenolysis include, for example, an arylsulfonyl group such as p-toluenesulfonyl; and a phenyl such as benzyl, trityl and benzyloxymethyl. Is a methyl group substituted by benzyloxy; arylmethoxycarbonyl groups such as benzyloxycarbonyl and 0-methoxybenzyloxycarbonyl;,,, trichloroethynoxycarbonyl, β-ethoxyethoxycarbonyl And a halogenoethoxycarbonyl group.

As the “ester”, those which can be converted to the free carboxylic acid form (I) of the present invention by being eliminated by chemical means or enzymatic means are suitable. Esters which can be converted into the corresponding free-form ruponic acid forms by chemical means such as hydrolysis include lower alkyl esters such as methyl esters and ethyl esters. Esters that can be converted to the corresponding free carboxylic acid form not only by chemical means but also by enzymatic means include, for example, acetomethyl ester, 1-acetoxityl ester, and bivaloylodimethyl ester Lower Al-Nyloxy Lower Alkyl esters; lower alkoxycarbonyloxy lower alkyl esters such as 1-ethoxycarbonyloxyethyl ester; aminoethyl esters such as 2-dimethylaminoethyl ester and 2-((1-piperidinyl) ethyl ester; 3-butyrolactonyl ester, coryne ester, phthalidyl ester, (5-methyl-2-oxo-1,3

-Dioxol-4-yl) methyl ester and the like.

As the salt of the compound (I) of the present invention, a pharmaceutically acceptable salt is particularly preferred, and trifluoroacetic acid, acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid, aspartic acid and glutamic acid are preferable. Salts with organic acids such as amino acids such as acid; salts with inorganic acids such as hydrochloric acid and phosphoric acid; metal salts such as sodium salt, potassium salt, zinc salt and silver salt; ammonium salts; Examples thereof include salts with organic bases such as trimethylamine, triethylamine, N-methylmorpholine, and the like.

Examples of the salt of the compound of the present invention (IE) useful as an intermediate include salts with inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid. Salts. The compounds (I) and (M) of the present invention sometimes exist as hydrates and solvates, and also exist as optically active isomers and stereoisomers (cis- and trans-forms). Sometimes. These compounds are also included in the present invention.

Among the compounds (I) of the present invention, preferred compounds are those included in the following general formula (I-IB).

Wherein R ₅ , G, T, X, Y and n have the above-mentioned meanings.

Further preferred compound (I) of the present invention is a compound included in the following general formula (IC).

[Wherein, R ₅ ′ is a cyclopropyl group, a 2,4-difluorophenyl group or a t_butyl group which may be substituted by fluorine, and X ′ is a hydrogen atom, a halogen atom or an amino group, T 'is _{CH, CF, CCC - 0CH 3} , a C-0CHF ₂ or nitrogen atom]

More specifically, the compounds described in Examples below are mentioned.

The following compounds and physiologically acceptable salts thereof are also suitable as the compound (I) of the present invention. 7— (1—amino-3—azabicyclo [3.2.0] hepatic 3—yl) 1—8—cyano 1—cyclopropyl—6—fluoro-1,4—dihydro-1—4—oxoquinoline I 3-Rubonic acid

7- (1-Amino-3-azabicyclo [3.2.0] hepatic 3-yl) _8_Bromo-1-cyclopropyl-6-fluoro-4-dihydro-4_oxoquinoline-3- carboxylic acid

7- (1-amino-3- 3-azabicyclo [3.2.0] hept-3-yl) 1-cyclopropyl-6-fluoro-1,4-dihydro 8-methyl 4-oxoquinoline 3-carboxylic acid

7— (1-amino-3-azabicyclo [3.2.0] hepter-3-yl) 1 1—cyclopropyl-6_fluoro-1,4,4-dihydro-4-oxo-1-8—trifluoromethylquinol 3-Carboxylic acid The compound (I) of the present invention can be produced, for example, by the following (a) amination reaction, (b) hydrolysis reaction and (c) ring closure reaction,

(a) Amination reaction

The compound (I) of the present invention, its ester and its salt are represented by the following general formula (I):

(In the formula, Pri has the meaning described above, and L is a leaving group bonded to Pri at the 7-position or the position corresponding to the 7-position of Pri. (However, the carboxyl group and the oxo group present in the pyridonecarboxylic acid residue represented by Pri may form a hydrogen chelate bond between these groups.)

A compound represented by the formula, its ester or its salt and the following general formula (IE)

Wherein R>, R ₂ , R ₃ , R 4 and n have the above-mentioned meanings.

When a boron chelate moiety is present in the product by reacting it with a bicyclic amide compound represented by the following formula, the product can be easily produced by hydrolyzing it.

The leaving group L in the general formula (H) includes, for example, a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, etc. Among them, a halogen atom such as fluorine-chlorine is preferable.

In this reaction, the compound (I) and the compound (IE) are reacted in an inert solvent at 10 to 180 ° C, preferably 20 to 130 ° C, preferably for 10 minutes to 24 hours. Can be carried out by stirring for 30 minutes to 3 hours. Solvents include water, methanol, ethanol, acetonitrile, Room temperature, pyridine, dimethylformamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone, and the like. These solvents are used alone or in the form of a mixture.

This reaction is generally carried out in the presence of an acid acceptor, using compound (ΠΙ) in an amount not equivalent to compound (H) or in excess. The compound (II) may be used in excess to serve as an acid acceptor. Acid acceptors include, for example, organic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] —7-ndenecene (DBU), pyridine, quinoline, picolin, and the like. Inorganic bases such as sodium, potassium hydroxide, sodium carbonate, carbon dioxide lime, sodium hydrogen carbonate, hydrogen carbonate lime and the like are preferred.

Compound (I) is known or can be produced according to a known method. The bicyclic amine compounds (II) are all novel, and their production methods will be described later.

(b) Hydrolysis reaction

Among the compounds (I) of the present invention, the carboxylic acid form can also be produced by subjecting a compound represented by the following general formula (IV) to a hydrolysis reaction.

[Wherein, u represents a group that can be converted to a carboxyl group by hydrolysis, and R ₂ , R ₃ , R ₄ , R ₅ , n, G, D, X, and D have the above-mentioned meanings]

Here, examples of U which can be converted into a carboxyl group include, for example, ester, cyano, amide, amidino, or a group represented by the formula —C (—NH) -〇—lower alkyl.

The hydrolysis reaction can be carried out by bringing the compound (W) into contact with water in an appropriate solvent. This reaction is usually carried out in the presence of a catalyst such as an acid or a base in the sense of accelerating the reaction. Examples of the acid catalyst that can be used include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, formic acid, and p-toluenesulfonic acid. Examples of the base catalyst include metal hydroxides such as sodium hydroxide and barium hydroxide, carbonates such as sodium carbonate and potassium carbonate, and sodium acetate.

As a solvent, water is usually used, but a water-miscible organic solvent such as ethanol, ethylene glycol dimethyl ether, benzene, or dioxane is used together with water depending on the properties of the compound (1). , 0 to 150 ° C, preferably 30 to 100 ° C. This reaction can also be carried out by directly heating compound (IV) in the presence of the aforementioned acid and then adding water.

(c) Ring closure reaction

Further, the compound (I) of the present invention has the following general formula (V)

[Wherein L ′ is a leaving group, and R ₅ ″ is a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl group, a heterocyclic group (these groups may be further substituted) G ′ represents CH or a nitrogen atom, T ″ represents C—Z or a nitrogen atom, wherein Z has the above-mentioned meaning, and R ₆ is a lower alkyl group, an aryl group or A benzyl group, and R ₂ , R ₃ , R ₄ , n, X and D have the same meaning as described above).

The leaving group L ′ here is preferably a group as described above for the leaving group L, particularly a halogen atom such as fluorine or chlorine.

In this ring closure reaction, 1 to 3 moles of a base, such as sodium carbonate, sodium hydride, and potassium t-butoxy, are used in an amount of 1 to 3 moles per mole of the compound (V). This is carried out by stirring a mixture of compound (V) and a solvent at 30 to 150 ° C, preferably 30 to 100 ° C for 1 to 6 hours in the presence of side, potassium fluoride, or the like. can do. As the solvent, ethanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like are suitable.

The compound (V) used as a raw material is also novel and can be produced, for example, according to the following reaction formula (1). Reaction formula (1)

[Wherein R ₆ ′ is a hydrogen atom or has the same meaning as R ₆ above, and R and R ₈ are the same or different and each represent a lower alkyl group, and R,, R _{_{_{2, R 3, R 4,}}} R 5 ", R ₆ , n, G ′, D ″, D, X, L and L ′ have the above-mentioned meanings.) The present invention produced by any one of the above (a), (b) or (c) When the compound (I) has an amino protecting group, the compound (I) of the present invention in which the amino protecting group is converted to a hydrogen atom by a hydrolysis reaction or a hydrogenolysis reaction, if desired. I can guide you.

The elimination reaction of the amino protecting group by hydrolysis can be carried out in the same manner as in the method described in the above method (b).

In addition, the elimination reaction of the amino protecting group by hydrogenolysis is advantageous by treating the compound (I) of the present invention having an easily hydrolyzable amino protecting group with hydrogen gas in a solvent in the presence of a catalyst. The compound can be converted to a compound of the present invention in which the amino protecting group is a hydrogen atom. Examples of the catalyst that can be used in this reaction include platinum, palladium, and Raney nickel. As the solvent, for example, ethylene glycol, dioxane, dimethylformamide, ethanol, acetic acid, water and the like can be used. This reaction can be carried out at 60 ° C or less, usually at room temperature.

When the easily hydrolyzable amino-protecting group is benzyl, trityl, benzyloxycarbonyl, p-toluenesulfonyl, etc., such a protecting group can be treated with sodium metal in liquid ammonia at 50 to 120 ° C. It can also be desorbed. In the above method (a), the compound (HI) used as a raw material is, for example, a compound represented by the following general formula (VI) R ₂ —

Wherein R ₉ and R ₁₀ each have the same meaning as or can be converted to R 3 and R ₄ , RH is an amino protecting group, R ₂ and n Has the above meaning)

The protecting group of the compound represented by is removed and converted to a hydrogen atom, and R ₉ and / or R ,. When is a group that can be converted into R ₃ and Z or R ₄ , R ₉ and or. Can be produced by converting into R ₃ and / or R ₄ .

Amino protecting group R! Examples of the, include the readily hydrolyzable amino-protecting group and the easily hydrolyzable amino-protecting group described above. When or R ₂ of the compound (VI) is an amino protecting group, the amino protecting group of RH should be different in character from the amino protecting group of R! Or R _2. Preferred for For example, when the amino protecting group of Ri or R _{2 is} a readily hydrolyzable amino protecting group such as t-butoxycarbonyl group, RH is preferably selected from a readily hydrolyzable amino protecting group such as benzyl ditrityl. Is done.

This elimination reaction can be carried out by subjecting compound (VI) to a hydrogenolysis reaction or a hydrolysis reaction described above.

In R ₉ and R ₁₀ , “a group that can be converted to R ₃ and R ₄ ” Examples include methanesulfonyloxy, p-toluenesulfonyloxy, benzyloxy, carboxy, carbamoyl, hydroxyminomethyl, benzylidene, cyclic acetal, dithioacetal, and the like.

Methanesulfonyloxyp-toluenesulfonyloxy can be converted to a halogen atom, a cyano group or a lower alkoxy group as R ₃ or R ₄ by nucleophilic or substitution reactions.

Benzoxy can be converted to a hydroxyl group as R ₃ or by a hydrogenolysis or hydrolysis reaction, and carboxy is converted to an acid halide, followed by a Wilkinson complex {RhCl [P (C ₆ H ₅ ) ₃ ] ₃ } Can be converted to a halogen atom as R ₃ or R ₄ . In addition, carbamoyldihydroxyaminomethyl can be converted to a cyano group as R ₃ or R 4 by treatment with thionyl chloride or chlorosulfonyl isocyanate, and benzylidene is converted to a cyclic acetal by oxidation. Can be converted into an oxo group as R ₃ or R ₄ by an acid-catalyzed hydrolysis reaction and dithioacetal by a hydrolysis reaction in the presence of mercuric chloride.

The compound (VI) is also novel, for example, Examples I to! It can be produced by the method described in Π or a method analogous thereto. The compound (I) of the present invention and its intermediate compound (II) thus produced can be isolated and purified according to a conventional method. These compounds can be obtained in the form of salts, free forms, or hydrates depending on the conditions of isolation and purification. Compounds can be prepared.

The stereoisomers of the compounds (I) and (ΠΠ) of the present invention can be prepared by a conventional method, for example, For example, they can be separated from each other by a fractional crystallization method, a chromatography method, or the like, and the optically active substance can be isolated by applying a known optical resolution method.

The thus-obtained compound (I) of the present invention and salts thereof are all novel compounds, exhibit excellent antibacterial activity, and are valuable as antibacterial agents. The compound (I) of the present invention and salts thereof can be used not only as human and veterinary medicines but also as fish disease medicines, agricultural chemicals, food preservatives and the like.

The ester form of the compound (I) of the present invention is valuable as a raw material for synthesizing the carboxylic acid form of the compound (I) of the present invention, but the ester form itself is easily converted into a carboxylic acid form in a living body. In some cases, it has the same action and effect as the carboxylic acid compound, and is also useful as an antibacterial agent.

Further, the compound (HI) of the present invention is useful as a direct intermediate of the compound (I) of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the in vitro and in vivo antibacterial activities of the compound (I) of the present invention will be described with reference to data below. The results are shown in Table 1. The numbers in the table indicate the minimum inhibitory concentrations (MIC; g / ml) measured according to the description in Chemotherapy 29 (1), 76 (1981). ₅ ; nig / kg).

The effect on mouse systemic infection (ED _5fl ; nig / kg) was as _follows : Intraperitoneal _{injection of 5} x 10 ³ viable bacteria (live bacteria) listed in Table 1 per Std-ddy male mouse (body weight: about 20 g) The test compound suspended in 0.4% carboxymethylcellulose was orally administered twice immediately after infection and 6 hours after infection. The survival rate of mice 7 days after infection was calculated by the Probit method. Examples of the control compound include piomidic acid, which is already commercially available as an excellent antibacterial agent, and 7_ (1-amino) having the following structure disclosed in Example 6 of the above-mentioned JP-A-64-56673. 3-Azabicyclo [3.1.0] hexar 3-yl) 1 1-Cyclopropyl-6,8-difluoro-1,4_dihydro σ-4 4-oxoquinoline-3-carboxylic acid.

Table 1 Antibacterial activity

Ph-F ₂ : 2,4-diflurescent π-phenyl Me: methyl As shown in Table 1 above, the compound (I) of the present invention exhibits excellent antibacterial activity both in vitro and in animal experiments. Especially in vivo-the compounds of the invention show better antibacterial activity than the comparative compounds.

Further, the compound (I) of the present invention has low toxicity and is useful as an antibacterial agent for mammals including humans, for prevention and treatment of bacterial diseases in mammals.

When the compound (I) of the present invention is used in humans as an antibacterial agent, the dosage varies depending on age, body weight, symptoms, administration route, etc. Generally, 5 mg to 5 g per day is administered once or several times. It is recommended that the drug be administered separately. The route of administration may be oral or parenteral.

The compound (I) of the present invention may be administered to humans or the like as it is, but is usually administered in the form of a preparation prepared together with pharmaceutically acceptable additives. Examples of such preparations include tablets, solutions, capsules, granules, granules, powders, syrups, injections, ointments and the like. These preparations can be produced using ordinary additives according to a conventional method. For example, as additives for oral use, carriers or diluents which are commonly used in the pharmaceutical field such as starch, mannite, crystalline cellulose, potassium propyloxymethylcellulose, water, and ethanol and do not react with the compound of the present invention are used. Used. Examples of additives for injection include those commonly used in the field of injections, such as water, physiological saline, glucose solutions, and infusions.

The above-mentioned liquid preparations and ointments can also be used for treatment and treatment in otolaryngology and ophthalmology. Next, the present invention will be described more specifically with reference to examples. Example I! Π relates to the method for producing the intermediate (ΠΙ), Examples 1 to 16 relate to the method for producing the target compound (I), and Example A relates to the method for preparing the pharmaceutical preparation. This is an example. Example I

1- (t-Butoxycarbonylamino) -1-3-azabicyclo [3.2.0] heptane

(A) 1-cyclobutene-1-carboxylic acid (J. Cem. So, p. 3002-1953) 35. lg is dissolved in 250 m 1 of methylene chloride, and the diphenyldiazomethane chloride is added thereto at room temperature. The methylene solution was dropped until the red color disappeared. After stirring at room temperature for 1 hour, dichloromethane was distilled off, and the resulting crude product was mixed with 500 ml of tetrahydrofuran, N-benzyl-N- (methoxymethyl) trimethylsilylmethylamine (Chem. Pharm. Bull. 93, 4 g, cesium fluoride 10.9 g, and trimethylsilyl triflate 15.9 g, and the mixture was heated at 60 ° C for 18 hours. The reaction mixture was cooled to 0 ° C, 35% aqueous sodium hydroxide (350 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The organic layer was separated, dried (anhydrous magnesium sulfate), and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 30: 1) and recrystallization (diisopropyl ether) to give 3-benzyl_1-diphenylmethoxycarbonyl. Go to Azabizicro [3.2.0] and get 52.lg. Melting point: 9 6 -9 9 ° C

^{_{] H-NMR (C DC1 3}} ) δ 1.69-2.32 (m, 4 H), 2.40-3.50 (m, 5 H), 3.71 (s, 2 H), 6.87 (s, 1 H), 7.17- 7.44 ( m, 1 5

H) IR (KB r) cm- ¹ : 1 7 2 0

MS (m / z): 398 (MH ⁺ )

(B) 45.8 g of the compound obtained in the above section (A) and 92 ml of a 20% aqueous sodium hydroxide solution were added to 700 ml of methanol, and the mixture was heated under reflux for 5 hours. After cooling, the mixture was neutralized by adding 20% hydrochloric acid, and concentrated under reduced pressure. Water and diisopropyl ether were added and stirred vigorously, and the aqueous layer was separated. And continuous extraction with black port Holm, dried (anhydrous magnesium sulfate), and dissolve the crude product obtained _c evaporating the black hole Holm in t-blanking evening Nord 4 5 0 ml, azide Jifue Niruhosuhoriru (DPPA) 88.2g and 32.4g of triethylamine

The mixture was heated under reflux for 15 hours. Then, the mixture was concentrated under reduced pressure, and ethyl acetate was added.

Washed twice with 0% aqueous sodium hydroxide solution. The organic layer was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from silica gel column chromatography (eluent n-hexane: ethyl acetate = 9: 1).

Purification by (n-hexane) gave 17.6 g of 3-benzyl-1- (t-butoxycarbonylamino) -13-azabicyclo [3.2.0] heptane. Melting point: 69-9 ° C

'H-NMR (CDC) (5: 1.42 (s, 9 H), 1.50-1.77 (m, 1 H), 2.03-2.45 (m, 5 H), 2.60-2.80 (m, 1 H), 2.73 ( d, 1 H, J = 9 Hz), 3.01 (d, 1 H, J = 9 Hz), 3.68 (s, 2 H), 4.73 (brs, 1 H), 7.19-7.41 (m, 5 H )

1 R (KB r) cm— ¹ : 3 380, 1685 MS (mZz): 303 (MH ⁺ )

(C) 5 g of the compound obtained in the above (B) was dissolved in 100 ml of ethanol, 1 g of -10% palladium carbon was added, and a theoretical amount of hydrogen was added. After the catalyst was removed by filtration, the solvent was distilled off, and the obtained crude crystals were recrystallized from n-hexanediisopropyl ether to give 1- (t-butoxycarbonylamino) -13-azabicyclo [3.2. 0] 3 g of heptane were obtained. Melting point: 1 13-1 16 ° C

^ -NMR (CDCh) δ 1.25-1.41 (m, 1 H), 1.45 (s, 9 H), 1.96-2.35 (m, 4 H), 2.65-2.87 (m, 3 H), 2.95-3.15 (m , 2 H), 4.82 (br, 1 H)

IR (KB r) cm- ¹ : 3294, 3185, 2982, 16992 MS (m / z): 213 (MH +) Example H

1-Methylamino-3 -azabicyclo [3.2.0] heptane (A) 3-benzyl_1-1- (t-butoxydicarbonylamino)-3-azabicyclo [3.2.0] heptane 6.8 g of methylene chloride 2 The mixture was dissolved in 0 ml, and 50 ml of trifluoroacetic acid was added, followed by stirring for 3 hours. After concentrating the reaction solution, an aqueous solution of sodium hydroxide was added thereto under ice cooling, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the chloroform was distilled off. The obtained crude product was dissolved in 47 ml of formic acid, and 17 g of anhydrous acetic acid was added dropwise over 90 minutes under ice cooling. Add ice water, and add sodium hydroxide aqueous solution under ice cooling The solution was added for neutralization, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.

Purification by means of-(eluent: chloroform: methanol = 30: 1) gave 3.1 g of 3-benzyl-1-formylamino-13-azabicyclo [3.2.0].

Ή-NMR (C DCh) δ: 1.61-1.82 (m, 1 H), 2.08-2.50 (m, 5 H), 2.61-3.14 (m, 3 H), 3.69 (s, 2 H), 5.90 (br , 1 H), 7.18— 7.42 (m, 5 H), 8.05 (d, 1 H, J = 2 H z)

IR (neat) cm ^-1 : 3270, 3028, 2940, 2791, 1659, 1530

MS (mZz): 2 3 1 (MH ⁺ )

(B) Dissolve 3.1 g of the compound obtained in the above (A) in 30 ml of toluene, add 20 ml of a 70% toluene solution of bis (2-methoxyethoxyquin) aluminum sodium hydride, and heat to reflux for 2 hours. did. After cooling, the reaction solution was slowly added to 20% sulfuric acid under ice-cooling, and insolubles were removed by filtration. The filtrate was adjusted to pH 11 by adding a 20% aqueous sodium hydroxide solution, and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 100: 1) to give 3_benzyl-1 monomethylamino 3-azabizhicrole. [3.2.0] 1.97 g of heptane was obtained.

^! H-NMR (CDCh) δ: 1.40-1.72 (m, 2H), 1.89-2.55 (m, 6H), 2.33 (s, 3Η), 2.79 (d, 1Η, J = 2ΟΟ) , 2.83 (d, 1Η, J = 2Ο Η ζ), 3.66 (s, 2Η), 7.18-7.43 (m, 5 H)

IR (neat) cm— ¹ : 3270, 2937, 2778

MS (mZz): 2 17 (MH ⁺ ), 18 7

(C) 1.95 g of the compound obtained in (B) above was dissolved in 30 ml of ethanol, 0.4 g of 10% palladium carbon and 2 ml of concentrated hydrochloric acid were added, and a theoretical amount of hydrogen was added at 50 ° C. . The catalyst was filtered off and washed with methanol. The solvent was distilled off. The residue was adjusted to pH 11 with an aqueous sodium hydroxide solution, and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.96 g of 1-methylamino-3-azabicyclo [3.2.0] heptane.

^] H-NMR (CDCh) δ: 1.21-1.45 (m, 1H), 1.77-3.00 (m, 10Η), 2.38 (s, 3H)

IR (neat) cm— ¹ : 3 2 7 0, 2 9 4 2, 1 6 9 2 Example HI

1 — (t-butoxycarbonylaminomethyl) 3-azabicyclo [3.2.0] heptane

(A) 3-benzyl-1-diphenylmethoxycarbonyl-13-azabicyclo [3.2.0] 13 g of heptane was dissolved in 100 ml of tetrahydrofuran, and 2.8 g of lithium chloride was added. After 2.5 g of sodium borohydride was added little by little, 30 ml of methanol was gradually added, followed by stirring at room temperature for 15 hours. After concentrating the reaction mixture under reduced pressure, add ice water and extract with ethyl acetate. did. After adding 10% hydrochloric acid and stirring vigorously, the aqueous layer was separated. A 10% aqueous sodium hydroxide solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane: acetone-2: 4: 1) to give 3-benzyl-1-hydroxymethyl-3-amine. Zabicyclo [3. 2. 0] heptane 5.4 g was obtained.

H—NMR (CDCh) δ: 1.64-2.19 (m, 6 H), 2.28—2.80 (m, 4Η), 3.52-3.77 (m, 4Η), 7.18—7.43 (m, 5Η)

1 R (neat) cm " ¹ : 3 3 4 6, 2 9 3 4, 2 7 8 5

MS (/ z): 2 18 (MH ⁺ )

(B) Dissolve 5.3 g of the compound obtained in (A) in 200 ml of tetrahydrofuran, add 7.1 g of triphenylphosphine, 5.2 g of getyl azodicarboxylate, and 7.4 g of diphenylphosphoryl azide in order. Stirred at room temperature for 48 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate and 10% hydrochloric acid were added, and the mixture was vigorously stirred, and then the aqueous layer was separated. A 20% aqueous sodium hydroxide solution was added to adjust the pH to 1, and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent n-hexane: ethyl acetate = 30: 1 to give 1-azidomethyl-3-benzyl-1-3). —Azabicyclo [3.

2.0] 5.4 g of heptane were obtained.

'H— NMR (CDC ") δ: 1.65-2.26 (m, 6 H), 2.39-2.52 (m, 1 H), 2.80 (d, 1Η, J = 9 Hz), 2.81 (d, 1Η) , J = 9 Η z), 3.37 (d, 1 H, J = 20 Hz), 3.43 (d, 1 H, J = 20 Hz), 3.64 (d, 1 H, J = 16.5 Hz), 3.71 (d, 1 H, J = 16.5 Hz), 7.18-7.44 (m, 5 H) IR (neat) cm- ,: 2 9 3 7, 2 7 8 7, 2 0 9 6

MS (m / z): 2 4 3 (MH ⁺ )

(C) 3.4 g of the compound obtained in (B) above was dissolved in 70 ml of tetrahydrofuran, 5.9 g of triphenylphosphine was added, and the mixture was stirred at 50 ° C for 2 hours. 55 ml of an 28% aqueous ammonia solution was added, and the mixture was stirred at 50 ° C for 3 hours. The organic layer was separated, and the aqueous layer was extracted with getyl ether. 1N Hydrochloric acid was added to the combined organic layers, and the mixture was vigorously stirred, and then the aqueous layer was separated. A 10% aqueous solution of sodium hydroxide was added to adjust the pH to 11, followed by extraction with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of tetrahydrofuran. To this, 7.7 g of di-t-butyl dicarbonate was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent n-hexane: ethyl acetate = 9: 1) and recrystallization (n-hexane) to give 3-benzyl-1- (t- (Butoxycarbonylaminomethyl) -1-3-azabicyclo [3.2.0] heptane 3.92 g was obtained. Melting point: 7 8-7 9 ° C

'Η-NMR (C DC ") 5: 1.44 (s, 9H), 1.64-2.47 (m, 7H), 2.72 (d, 1H, J2 9Hz), 2.74 (d, 1H, J = 9 Hz), 3.20 (dd, 1 H, J = 23 Hz, 6 Hz), 3.28 (dd, 1 H, J = 23 Hz, 6 Hz) IR (KB r) cm " ¹ : 3372, 2972. 2932, 2797, 1688, 1530

MS (m / z) 3 1 7 (MH +), 2 5 9

(D) 2.9 g of the compound obtained in (C) above was dissolved in 6 Ond of ethanol, 0.6 g of 10% palladium carbon was added, and a theoretical amount of hydrogen was added at 50 ° C. After the catalyst was removed by filtration, the solvent was distilled off, and the resulting crude crystals were recrystallized from n-hexane-diisopropyl ether to give 1- (t-butoxycarbonylaminomethyl) -13-azabicyclo [3. 2. 0] 1.58 g of heptane _c melting point: 83_86 ° C

IR (KB r) cm " ¹ : 3 3 1 1, 3 19 2, 29 60, 1720, 1 55 56 Example 1

7 _ (1 -amino-3-azabicyclo [3.2.0] hept-3-yl) 1-cyclopropyl-1, 8-difluoro-1,4-dihydro-4- 4-oxoquinoline-1 3 Carboxylic acid (A) 1- (t-butoxydicarbonylamino) 1-3-azabicyclo

[3.2.0] Heptane 1.9 g, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro 4-oxoquinoline-13-caprolubonic acid 0.83 g was added to 15 ml of pyridine and 4 hours Heated to reflux. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 100: 1) and recrystallization (ethyl acetate-diisopropanol), and 0.99 g of 0.77 [1 — (t-butoxyca (Rubonylamino) 1-3-azabicyclo [3.2.0] hept-3-yl] 11-cyclopropyl-16,8-difluoro-1,4-dihydro 4-oxoquinoline-13-carboxylic acid ( Melting point 2 1 1 —2 15 ° C) _c (B) Dissolve 0.97 g of the compound obtained in the previous section (A) in 35% hydrogen chloride / ethanol solution 20 m 1 and heat at 80 ° C. Heated for 10 minutes. The reaction mixture was concentrated under reduced pressure, acetonitrile and getyl ether were added, and the precipitated crystals were collected by filtration. Purification by CHP—20P column chromatography (eluent: water: acetonitrile: = 7: 3) yielded 244 mg of the desired product (melting point: 242-247 ° C (decomposition)). Was. Example 2

7— (1—Amino-3-3-azabicyclo [3.2.0] heptyl-3-yl) 1—8-Chloro-1—cyclopropyl-1 6—fluoro-1,4-dihydro 4—oxoquinoline — 3 —Trifluoroacetic acid salt

(A) 1-(t-butoxycarbonylamino)-3-azabicyclo [3.2.0] heptane 1.22 g, 8-chloro-1-cyclopropyl-1, 7-difluoro-1, 4-dihydro-1-4- 0.96 g of oxoquinoline-13-carboxylic acid and 0.58 g of 1,8-diazabicyclo [5.4.0] -17-decene were added to 20 ml of acetonitrile, and the mixture was heated under reflux for 3.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; liquid form: methanol = 100: 1) and recrystallization (ethyl ethyl diisopropyl acetate) to give 0.96 g of 7- [ 1 _ (t-butoxycarbonylamino) 1-3-azabicyclo [3.2.0] hepter 3-yl] 18-chloro-1-cyclopropyl-16-fluoro-1, 4—Dihydro 4-oxoquinoline-3-carboxylic acid (melting point 200—2

0 2 ° C).

(B) 0.94 g of the compound obtained in the above (A) was dissolved in 10 ml of methylene chloride, 20 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, acetonitril and geethylether were added, and the precipitated crystals were collected by filtration. After washing with acetonitrile, 65 mg of the desired product [melting point: 236-240 ° C (decomposition)] was obtained. Example 3

7— (1—amino-3-3-azabicyclo [3.2.0] hepatic 3-yl) 1-cyclopropyl-1-6-fluoro-1,4-dihydro-8-methoxy-4-1-oxoquinoline 3-Rubonic acid trifluoroacetate (A) 1- (t-butoxycarbonylamino) 1-3-azabicyclo

[3.2.0] heptane 1.07 g, 1-cyclopropyl-1,6,7-difluoro-1,4, dihydro-1-8-methoxy-4-oxoquinoline-1,3-force rubonic acid—BF ₂ —chelate 1.15 g and 0.68 g of triethylamine was added to 18 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 16 hours. Water was added, the mixture was extracted with chloroform, and the solvent was distilled off. To the obtained residue, 300 ml of 80% ethanol water and 50 ml of triethylamine were added, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 100: 1) and recrystallization (ethyl acetate-diisopropyl ether) to obtain 1.17 g of 7- [1-(t-butoxycarbonylamino)-3-α Zabicyclo [3.2.0] hepter 3-yl] 1-cyclopropyl

There was obtained 6-fluoro-4-dihydro-8-methoxy-4-oxoquinoline-13-carboxylic acid (melting point 211-21 ° C). (B) In the same manner as in Example 2 (B), the desired product [melting point 230-235 ° C (decomposition)] was obtained from the compound obtained in the above (A). Example 4

The reaction and treatment were carried out in the same manner as in Example 2 to obtain the compounds shown in Table 2 below.

Table 2

Boc: t-butoxyl / ke hill Ph-F ₂ : 2,4-difluorophenyl Me: methyl t-Bu: t-butyl Example 1 2-1 6

Reaction and treatment were performed in the same manner as in Example 3 to obtain the compounds shown in Table 3 below.

Boc: t-butoxycarbonyl Me: methyl

Example A: Tablet manufacturing method

Compound of Example 1 or 2 250 g Corn starch 54 g Carboxymethylcellulose C a 40 g Microcrystalline cellulose 50 g Magnesium stearate 6 g The above components were mixed with ethanol, granulated by a conventional method, and tableted to obtain 100,000 tablets having a weight of 400 m. Industrial applicability

As described above, the compound (I) of the present invention is useful as a pharmaceutical (antibacterial) for mammals including humans, and the compound (m) of the present invention is a direct intermediate for synthesizing the compound (I). Useful as

Claims

Claims The following general formula (I)

A-P r i (I)

[In the formula, P ri is a pyridonecarboxylic acid residue, and A is the following formula (C) bonded to the 7-position or a position corresponding to the 7-position of the pyridonecarboxylic acid.

.

R ₂ — ヽ N

(CH ₂ ) n (C)

4 N-R

Wherein R and R ₂ are the same or different and each represents a hydrogen atom, a lower alkyl group or an amino protecting group, and R ₃ and R ₄ are the same Or different, each means a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an oxo group, a lower alkoxy group or a lower alkyl group, and n represents an integer of 0 or 1.)

A pyridonecarboxylic acid derivative substituted by a bicyclic amino group represented by the formula:, an ester thereof, and a salt thereof. 2 P ri is the following formula

[Wherein, R ₅ represents a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl group, or a heterocyclic group (these groups may be further substituted), and G represents C— E or a nitrogen atom, where E is a hydrogen atom or forms a bridge represented by one S_CH (CH ₃ ) — together with R _5, and T is a C-Z or nitrogen Z represents a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkyl group or a halogeno lower alkyl group, or Z together with R ₅ X represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or an amino group which may be protected, and D represents a cross-linking represented by _〇 -CH ₂ -CH (CH ₃ ) —. C-Y or nitrogen atom, where Y is a hydrogen atom Or a halogen atom)

The pyridonecarboxylic acid derivative substituted with a bicyclic amino group according to claim 1, which is a pyridonecarboxylic acid residue represented by the following formula: 3 General formula below

[In the formula, n has the meaning described in claim 1, R ₅ , G −

T, X and Υ have the meanings described in claim 2) .A pyridonecarboxylic acid derivative substituted with a bicyclic amino group according to claim 1 or 2 represented by the following formula: Its salt.

4 General formula below

[In the formula, R ₅ ′ is a cyclopropyl group, a 2,4-difluorophenyl group or a t-butyl group which may be substituted by fluorine, and X ′ is a hydrogen atom, a halogen atom or an amino group. And T 'is CH, CF, CCK C-OCHs. C-OCHF2 or a nitrogen atom.)

4. The pyridonecarboxylic acid derivative substituted with a bicyclic amino group according to claim 1, 2 or 3, represented by the formula:

5 The following general formula (III)

(Wherein, R,, R ₂ , R ₃ , R ₄ and n have the meaning described in claim 1)

And a salt thereof.

6. The bicyclic amine compound according to claim 5, wherein R, R ₂ , R ₃ and R ₄ are all hydrogen atoms, and n is 0, and a salt thereof.

7 The following general formula (I)

A-P r i (I)

[Wherein, Pri and A have the meanings described in claim 1] An antibacterial agent comprising a pyridonecarboxylic acid derivative substituted with a bicyclic amino group represented by the formula: or an ester or a salt thereof as an active ingredient. 8 The following general formula (I)

A-P r i (I)

(Wherein, P r i and A have the meanings described in claim 1)

An antibacterial composition comprising a pyridonecarboxylic acid derivative substituted with a bicyclic amino group represented by the formula: or an ester or a salt thereof, and a pharmaceutically acceptable additive.

9 The following general formula (I)

A-Pri (I) (wherein, Pri and A have the meanings described in claim 1)

A method for producing an antibacterial composition, comprising mixing a pyridonecarboxylic acid derivative substituted with a bicyclic amino group represented by the formula (I), its ester or a salt thereof, and a pharmaceutically acceptable additive.

10 The following general formula (I)

A-P r i (I)

(Wherein, P r i and A have the meanings described in claim 1)

A pyridonecarboxylic acid derivative substituted with a bicyclic amino group represented by the formula: or an ester or a salt thereof to a mammal. Method for treating bacterial diseases of products c

11 (a) The following general formula (H)

L-P r i (I)

Wherein, P ri has the meaning described in claim 1, L is a leaving group bonded to P ri at the 7-position or a position corresponding to the 7-position of P ri, The carboxyl group and oxo group present in the pyridone carboxylic acid residue represented by may form a boron chelate bond between these groups.)

A compound represented by the formula, its ester or its salt and the following general formula (m)

Is reacted with a bicyclic amide compound represented by the formula (1), and if a boron chelate moiety is present in the product, it is hydrolyzed or (b) The following general formula (N)

Wherein, U represents a group convertible to a carboxylic group by hydrolysis,, R ₂ , R ₃ , R ₄ and n have the meanings of claim 1, and R ₅ , G , T, X and D have the meaning described in claim 2)

The ability to hydrolyze the compound represented by and convert the substituent U to a carboxyl group, or

(c) The following general formula (V)

Wherein, L 'is a leaving group, Ι¾ ₅ Ί or a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, Fuweniru group, a heterocyclic Shikimoto (these groups may be further substituted) Means G 'denotes CH or nitrogen atom, T "means C one Z or nitrogen atom, wherein Z has the meaning according claim 2, R ₆ is a lower alkyl group, Ariru Group or benzyl group, Ri Rz Rs Rd iu X and D have the meanings given above.)

Subjecting the compound represented by to a ring closure reaction; and

(d) if a protecting group is present in the resulting compound, if necessary, remove it; and, if necessary,

(e) When free form is obtained, convert to salt, and when salt is obtained, convert to free form

A process for producing a pyridonecarboxylic acid derivative substituted with a bicyclic amino group represented by the general formula (I) according to claim 1 or an ester or salt thereof.

12 (a) The following general formula (^)

Wherein R ₉ and. Is a group which has the same meaning as, or can be converted into, R ₄ and R _{4 in} Claim I, RH is an amino protecting group, R,, R ₂ and n has the meaning described in claim 1)

Into a hydrogen atom, and their, R _s and Z or R, the Amino protecting group R !, eliminated the compound represented by. R ₉ and Z or R, when is a group which can be converted into R ₃ and Z or R ₄ . To R ₃ and / or R ₄ and

(b) when R, and Z or R ₂ in the obtained compound are amino protecting groups, if necessary, remove them, and if necessary,

(c) When free form is obtained, convert to salt, and when salt is obtained, convert to free form

6. A method for producing a bicyclic amine compound represented by the general formula (IE) according to claim 5, or a salt thereof.